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Effects of halothane on the transient outward K(+) current in rat ventricular myocytes
L A Davies1, P M Hopkins, M R Boyett
1School of Biomedical Sciences, University of Leeds, Leeds, LS2 9NQ.
Insights
Halothane significantly inhibits the transient outward potassium current (I(to)) in cardiac cells. This anesthetic affects I(to) inactivation and may contribute to halothane
Area of Science:
- Cardiac Electrophysiology
- Anesthesiology
- Ion Channel Modulation
Background:
- Halothane is known to affect cardiac membrane currents, but its impact on the transient outward potassium current (I(to)) is poorly understood.
- I(to) plays a crucial role in cardiac repolarization and action potential duration.
Purpose of the Study:
- To investigate the effects of halothane on the transient outward potassium current (I(to)) in rat ventricular myocytes.
- To determine the concentration-dependence and specific properties of halothane's interaction with I(to).
Main Methods:
- Whole-cell patch-clamp recordings were performed on isolated rat ventricular myocytes.
- The 4-aminopyridine sensitive component of I(to) was isolated and measured under varying halothane concentrations.
- Calcium currents (I(Ca)) were blocked using Cd(2+) or nifedipine.
Main Results:
- Halothane significantly inhibited I(to) in a concentration-dependent manner, with an estimated K(0.5) of 1.1 mM.
- A concentration of 1 mM halothane shifted the steady-state inactivation curve of I(to) by 16 mV towards negative potentials.
- Halothane accelerated the inactivation rate of I(to), reducing the time constant from 14 ms to 9 ms.
Conclusions:
- Halothane reduces I(to) by altering its inactivation properties, a finding relevant at clinical concentrations.
- The inhibition of I(to) by halothane may influence cardiac refractoriness and contribute to its arrhythmogenic potential.
Abstract:
1. Halothane has been shown to affect several membrane currents in cardiac tissue including the L-type calcium current (I(Ca)), sodium current and a variety of potassium currents. However, little is known about the effects of halothane on the transient outward K(+) current (I(to)). 2. Single ventricular myocytes from rat hearts were voltage clamped using the whole cell patch configuration and an EGTA-containing pipette solution to record the Ca(2+)-independent, 4-aminopyridine sensitive component of I(to). 300 microM Cd(2+) or 10 microM nifedipine was used to block I(Ca). 3. At +80 mV, I(to) (peak current minus current at the end of the pulse) was 1.8+/-0.2 nA under control conditions which was reduced to 1.3+/-0.2 nA by 1 mM halothane (P:<0.001, mean+/-s.e.mean, n=9). The inhibition of I(to) by halothane was concentration-dependent (K(0.5), 1.1+/-0.2 mM). 4. One mM halothane led to a 16 mV shift in the steady-state inactivation curve towards negative membrane potentials (P:=0.005, n=8) but had no significant effect on the activation-voltage relationship (P:=0. 724). One mM halothane also increased the rate of inactivation of I(to); the dominant time constant of inactivation was reduced from 14+/-1 to 9+/-1 ms (P:=0.017, mean+/-s.e.mean, n=6). 5. These data show that halothane reduced I(to); 0.3 mM, close to the MAC(50) value for halothane, inhibited the current by 15% and as such, the inhibition of I(to) will be relevant to the clinical situation. Halothane induced a shift in the steady-state inactivation curve and accelerated the inactivation process of I(to) which could be responsible for its inhibitory effect. 6. Due to the differential transmural expression of I(to) in ventricular tissue, inhibition of I(to) would reduce the transmural dispersion of refractoriness which could contribute to the arrhythmogenic properties of halothane.